1. Field of the Invention
This invention relates to small molecule benzoxazole compounds useful as inhibitors of Hepatitis C Virus.
2. Background of the Invention
Hepatitis C Virus (HCV) affects approximately 170 million people worldwide. The blood-born illness has clinical symptoms that are generally benign or subacute, leaving patients without knowledge of the disease until it is manifested as chronic liver damage 1-3 decades later. Infection can lead to liver damage, cirrhosis of the liver, liver cancer, and liver failure.
An enveloped virus belonging to the Flaviviridae family, HCV has a positive strand RNA genome of approximately 10 kilobases that encodes a polyprotein of approximately 3000 amino acids. The N-terminus of the polyprotein is cleaved into three structural proteins (core, E1, E2) and the C-terminus is cleaved into seven mature nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). The NS3 protein is a promising target for intervention due to its enzymatic activities, acting as a serine protease, an RNA-stimulated nucleoside triphosphatase (NTPase) and an RNA helicase. HCV helicase activity is essential for viral replication and requires Mg2+ and ATP. In the genomic process, Flaviviridae viruses synthesize negative-stranded RNA using the parentally positive-stranded RNA as a template. The resulting negative-stranded RNA is used as the template to synthesize a positive-stranded progeny RNAs that are assembled into viral particles.
Therapies for HCV have primarily focused on reverse transcriptase and protease, two of the three virally-encoded enzymes. These are not effective in all patients, with the virus remaining active in some host tissues. The current treatment of peginterferon and ribavirin achieves only a 40-50% sustained viral response (SVR) rate. Moreover, the vast majority of the patient have to prematurely halt treatment due to complications arising from undesirable side effects. Therefore, new treatments are needed that are more effectual and better tolerated.